Since the cultivation of cells ex vivo was discovered in the early twentieth century cell culture has matured from a simple, microscope driven, observational science to a universally acknowledged technology with roots, which are set as deep in academia as they are in industry. Recent advances in cell therapies and tissue engineering are paving the road to regenerative medicine. The goals of this field include replacing, repairing and regenerating tissues and organs. Furthermore, medical treatment with cell-based products and procedures often lead to better therapeutic results than available pharmaceutical drugs or medical devices.
Today cells of many human tissues can be cultured ex vivo. Numerous biotechnology companies have been pursuing projects over more than ten years to commercialize cell-based products on a fee-for-service basis; however, most with very limited success. Among the hurdles are the high costs associated with Good-Manufacturing-Practice compliant manufacturing. Notably, manufacturing of innovative cellular therapeutics is still generally dependent on manual operation and manual control of traditional cultivation systems.
Partially automated bioreactor systems have been developed typically for the production of high density cultures of a single cell type often used with automatically regulated medium flow, oxygen delivery, temperature control. In such bioreactors once the cell culture was set up, the process runs with little manual intervention, thus limiting sources of contamination of the cell culture; yet, the set-up, process monitoring and harvesting procedures are still performed manually. However, there is also a demand for more complex cell culture processes yielding three-dimensional cell tissues and or multiple cell types grown in one cell culture.
EP 0,832,182 describes an improved bio-manufacturing system termed Replicell-System by Aastrom Biosciences. The Replicell-System is a modular system for automated cell expansion over a fixed time period comprising a cell processor, a system manager, individual incubator units, as well as patient-specific disposable cultivation cassettes with electronic application keys. Advantages of this system is the relatively high degree of automation with respect to proliferation of bone marrow derived cells if compared with manual proliferation of such cells over one or more passages using traditional T-flask approaches. Once initial cell seeding within the proliferation bioreactor is done, the following cell growth in a closed Replicell bioreactor system over a pre-defined cultivation period including media exchange is achieved in a largely automated manner. One major disadvantage of the system, however, is its limited flexibility. The Replicell automated cell manufacturing system is very much tailored to Aastrom's patented “single-pass perfusion” cell culture technology for stem cell and hematopoietic cells production as described in U.S. Pat. No. 5,763,266. Human stem and/or hematopoietic cells are grown to large quantities over one passage, only. The Replicell system, designed for this purpose, provides the combination of appropriate bioreactors and the execution of subtle single passage cell culture protocols with appropriate levels of nutrients and growth factors while simultaneously removing undesirable metabolic products. In contrast, the majority of cell-based and cell-derived medical therapeutics still require protocols with multiple passages, where an initial small number of cells is being expanded over several passages. The Replicell-System is not flexible enough to allow expansion of cells over more than one passage. Further, even for this single-passage-only cell culture protocol the Replicell system exhibits a very complex but still only partially automated mechanism to achieve proliferation of cells: Two different and independent devices are required for automated handling of cell proliferation whereas the transition from one device to the other still demands manual skill and handling. Furthermore, the continuous monitoring of critical cell growth parameters such as pH and O2 by means of biosensors is not possible with the Replicell-System, and most importantly this manufacturing system does not provide such important bioprocessing steps as biopsy digest, cell wash, cell concentration, and cell differentiation.
WO 03087292 and WO 05116186 describe a tissue engineering system termed ACTES system from Millenium Biologix. The ACTES system has been designed to include a wider set of linked bioreactor and other system compartments to address a variety of bio-processing events such as biopsy digest, cell proliferation, cell wash and cell collection as well as the differentiation, including thus the possibility for de novo tissue formation. Also the possibility of monitoring cell cultivation parameters such as pH and O2 during processing has been integrated allowing a constant monitoring over the cultivation process. However, despite enabling the automation of several cultivation processes, the ACTES system like the Replicell system provides only one cell growth chamber with a pre-defined size/volume ratio. As a consequence the ACTES system, too, is tailored to only very few highly specific applications, such as the production of cartilage tissue from a small number of cells obtained from a cartilage biopsy. For successful cartilage tissue production using the ACTES System it is even required to have access to a proprietary growth factor cocktail (U.S. Pat. No. 6,582,960 entitled “Use of fibroblast growth factor 2 for expansion of chondrocytes and tissue engineering”).
Thus, it is the object of the current invention to provide an automated cell culture arrangement using a closed system approach, which is suited for a wide variety of cell culture protocols. In particular, it is an object of the invention to provide an automated cell culture arrangement, for which standard established manual cell culture protocols can be adapted easily including more-than-one-passage cell culture protocols. And yet a further object of the invention is to provide an automated cell culture arrangement comprising different modules such that a tailor-made automated cell culture arrangement can be assembled according to the needs of a particular application and setting. Further objects of the invention include providing specialized tool modules for an automated cell culture arrangement (microscope, centrifuge).